Isoquinoline and quinazoline urea analogues as antagonists for the human adenosine A(3) receptor

• Published in: Journal of medicinal chemistry Vol. 43; no. 11; pp. 2227 - 2238
• Main Authors: van Muijlwijk-Koezen, JE, Timmerman, H, van der Goot, H, Menge, WMPB, Kunzel, JFV, de Groote, M, IJzerman, AP
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 01.06.2000
• Subjects: Animals; Binding Sites; Cells, Cultured; Cerebral Cortex - cytology; Chemistry, Medicinal; CHO Cells; Cricetinae; Humans; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Models, Molecular; Pharmacology & Pharmacy; Purinergic P1 Receptor Antagonists; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Rats; Receptor, Adenosine A3; Receptors, Purinergic P1 - metabolism; Science & Technology; Structure-Activity Relationship; A2; POTENT; LIGANDS; AFFINITY; CLONING; MAST-CELLS; A3-ADENOSINE RECEPTOR; DERIVATIVES; EXPRESSION
• ISSN: 0022-2623
• DOI: 10.1021/jm000002u

Isoquinoline and quinazoline urea derivatives were found to bind to human adenosine A(3) receptors. Series of N-phenyl-N'-quinazolin-4-ylurea derivatives and N-phenyl-N'-isoquinolin-1-ylurea derivatives were synthesized and tested in radioligand binding assays on their adenosine receptor affinities. A structure-affinity analysis indicated that on the 2-position of the quinazoline ring or the equivalent 3-position of the isoquinoline ring a phenyl or heteroaryl substituent increased the adenosine A(3) receptor affinity in comparison to unsubstituted or aliphatic derivatives. Furthermore, the structure-affinity relationship of substituted phenylurea analogues was investigated. Substituents such as electron-withdrawing or electron-donating groups were introduced at different positions of the benzene ring to probe electronic and positional effects of substitution. Substitution on the 3- or 4-position of the phenyl ring decreased the adenosine A(3) receptor affinity. Substitution at position 2 with an electron-donating substituent, such as methyl qr methoxy, increased human adenosine A(3) receptor affinity, whereas substitution on the 2-position with an electron withdrawing -substituent did not influence affinity. Combination of the optimal substituents in the two series had an additive effect; which led to the potent human adenosine A(3) receptor antagonist N-(2-methoxyphenyl)-N'-(2-(3-pyridyl)quinazolin-4-yl)urea (VUF5574, 10a) showing a K-i value of 4 nM and being at least 2500-fold selective vs A(1) and A(2A) receptors. Compound 10a competitively antagonized the effect of an agonist in a functional A3 receptor assay, i.e., inhibition of cAMP production in cells expressing the human adenosine A3 receptor; a pA(2) value of 8.1 was derived from a Schild plot. In conclusion, compound 10a is a potent and selective human adenosine A(3) receptor antagonist and might be a useful tool in further characterization of the human A(3) receptor.